The overall objectives are to identify toxins other than ammonia which cause depression of nervous system in hepatic encephalopathies, and to characterize their biochemical actions. These studies will include: (A) Biochemical investigations on Reye's syndrome and the vomiting sickness of Jamaica (Hypoglycin A intoxication): Biochemical mechanism of these similar, acute hepatic encephalopathies will be investigated to characterize a specific biochemical relationship between liver and brain. Experimental hypoglycin intoxication in animals will be extensively studied as a model. Biochemical effects of isovaleric acid, a short chain fatty acid, and several dicarboxylic acids, which have been identified by us in blood and urine of hypoglycin A-treated animals, will be tested in vitro and in vivo. Attempts will be made to isolate and identify possible toxins from clinical specimens from patients with Reye's syndrome. (B) Biochemical investigations on hepatic coma from other causes: We will extend these studies to hepatic coma from other causes and attempt identification of possible toxins other than ammonia from urine, blood and cerebrospinal fluid. BIBLIOGRAPHIC REFERENCES: Ampola, M.G., Mahoney, M.J., Nakamura, E., and Tanaka, K. Prenatal therapy of a patient with vitamin B12-responsive methylmalonic acidemia. New Engl. J. Med. 293:314-317, 1975. Tanaka, K. Disorders of organic acid metabolism in Biology of Brain Dysfunction, Gaull, G.E., ed., Plenum Publ. Co., New York, Vol. 3, pp 145-214, 1975.